Cancer chemotherapy generally aims to slow the growth of, or destroy, cancer cells while avoiding collateral damage to surrounding cells and tissues; the most effective anticancer agents are best able to selectively target cancer cells while leaving normal cells relatively unaffected. Some ether lipids can be effective as anticancer agents in animals (see for example, Dietzfelbinger et al. (1993); Zeisig et al. (1993); Powis et al. (1990); Berdel (1991); Bhatia and Hadju (1991); Reed et al. (1991); Workman (1991); Workman et al. (1991); Bazill and Dexter (1990); Berdel (1990); Counsell et al. (1990); Tritton and Hickman (1990); Muschiol et al. (1990); Layton et al. (1980); Runge et al. (1980); Munder & Westphal (1990); Lohmeyer & Workman (1995); Lohmeyer & Bittman (1994); Great Britain Patent No. 1,583,661, Pat. No. 3,752,886).
It is speculated that the lack of alkyl cleavage enzyme expression in cancer cells is responsible for the failure of these cells to hydrolyze and remove the ether lipids, and hence, for the accumulation of the lipids in these cells. This intracellular ether lipid accumulation leads to the disturbance of cell membrane lipid organization by a detergent-like activity of ether lipids. Membrane structure, and hence, cell stability, can be disrupted by this activity.
Normal cells typically possess the alkyl cleavage enzymes required to hydrolyze ether lipids and hence, to prevent their intracellular accumulation. However, normal cells which do not possess the requisite levels of the enzymes, e.g., red blood cells ("RBCs") are subject to the same disruptive effects of ether lipid action as are cancer cells. Hemolysis, which results from exposure of RBCs to ether lipids having detergent-like activity can be a major drawback to therapeutic use of the ether lipids (see, for example, Houlihan et al., 1995).
A number of different approaches are potentially available for decreasing or eliminating such drug-induced toxicity. One approach is to incorporate the drugs into lipid-based carriers, e.g., liposomes. Such carriers can buffer drug toxicity, for example, by sequestering the drug in the carrier such that the drug is unavailable for inducing toxicity. Lipid carriers can also buffer drug-induced toxicity by interacting with the drug such that the drug is then itself unable to interact with the cellular targets through which it exerts its cytotoxic effects. The carriers also maintain the ability of the drugs to be therapeutically effective when released therefrom, e.g., when the carriers are broken down in the vicinity of tumors.
However, the organization and packing arrangements of lipids in lipid-based carriers, e.g., liposomal bilayers, is similar to lipid organization and arrangement in cell membranes. Accordingly, a drug, such as an ether lipid, believed to exert its toxic effects, at least in part, by disrupting cell membrane lipid organization, have the same type of adverse effect on the lipid based carrier. In such cases, for the lipid-based structure to be effective as a carrier it must be formulated such that the toxicity-inducing drug cannot disrupt the carriers structure, but nevertheless is maintained in a form so that, when released from the carrier, the drug is then therapeutically effective.
This invention provides a formulation comprising a lamellar lipid which comprises an ether lipid and a lipid of complementarily molecular shape to the ether lipid. The shape complementarity brought about by the combination of these lipids in a lamella inhibits ether lipids possessing detergent-like activity from exercising it on the lamellae of the carrier. Nevertheless, when the lamellae reach the intended sites of therapeutic action and are then broken down, the ether lipids are released in a therapeutically effective form.
PCT/US95/12721 describes liposomes containing cholesterol, a phosphatidylcholine and a phosphatidylethanolamine-dicarboxylic acid derivative, in addition to a glycerol-based ether lipid having a methoxy group attached to the second position of the glycerol backbone. German Patent Application No. 4,132,345 describes liposomes containing cholesterol and a positively charged lipid in addition to a methoxy group-containing ether lipid. Japanese Patent Application No. 61-022,020 describes liposomes containing cholesterol and a phospholipid in addition to an acetyl, or propionyl, group-containing glycerol-based ether lipid. Mende et al. describes the membrane potential altering effects of liposomes containing an ether lipid/cholesterol combination of an equimolar ratio. However, none of these documents describes pharmaceutical compositions containing glycerol-based ether lipids having a methoxy group at the second position, or the use of such compositions in the treatment of various cancers and inflammatory conditions, amongst other disorders.